DigitalUM :: Browsing by Subject "Tumor progression"

Browsing by Subject "Tumor progression"

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Open Access
agged tumor cells reveal regulatory steps during earliest stages of tumor progression and micrometastasis
(Murcia : F. Hernández, 1999) Culp, L.A.; Lin, W.C.; Kleinman, N.R.
Histochemical marker genes were used to "tag" mouse fibrosarcoma or human neuroblastoma cells, providing a better understanding of their subsequent progression and metastasis mechanisms in nude mice. Micrometastases in the lung were initiated from clusters of 2-6 cells rather than single cells in most cases; tumor cells were also visualized binding to the endothelium of small blood vessels to initiate these micrometastases. Shortterm, these mechanisms relied heavily on fluidity of cell surface proteins, rather than nuclear events. Micrometastases in some organs were transient and never became established. Angiogenesis was visualized in both primary tumor systems via "fixation" of the animal's circulation; very small microvessels were growing toward the primary tumor as soon as 48-72 hours post-injection. Marker genes were also valuable for quantitating genetic instability of specific tumor cell populations and potential gene regulatory mechanisms operating in specific organ sites. These latter studies have direct relevance to the significance of N-myc oncogene amplification in neuroblastoma during progression and CD44 gene plasticity of expression in fibrosarcoma during metastasis. Marker gene-tagged single tumor cells can now be analyzed for gene regulatory events in virtually any organ and in combination with laser capture microdissection and other high-resolution methodologies, providing insight into the very earliest gene-regulatory events during micrometastasis.
Open Access
Assessment of cumulated genetic alterations in colorectal cancer
(Murcia : F. Hernández, 2003) Risques, R.A.; Ribas, M.; Peinado, M.A.
Widespread genetic alterations are a common feature of most colorectal cancers. While specific recurrent alterations may reveal the involvement of a gene or set of genes in the biology of the disease, the cumulated genomic damage is likely to reflect the biological history of the neoplastic cells. Furthermore, the functional implications behind many of these genetic changes may show the evolutionary potential of the neoplastic cells. Different approaches, ranging from the gross determination of total nuclear DNA content to cytogenetic and molecular approaches, reveal different types of chromosomal and subchromosomal alterations and have been applied to measure generalized genomic damage in colorectal carcinomas. High levels of genomic damage usually appear associated with increased aggressiveness in colorectal cancer, and the use of different assessments of genomic damage as independent prognostic factors has been proposed. Therefore, appropriate definition of the extent of cumulated alterations and their functional consequences may be of interest in the understanding and management of cancer. The different methodologies and clues to the interpretation and integration of the results obtained with each technique are discussed in this review.
Open Access
Crumbs3: Expression and biological significance in normal and neoplastic tissues
(2026) Akane Kitta-Kunihiro; Chiemi Ikude; Eisaku Kondo; Hidekazu Iioka; Biología Celular e Histología; Universidad de Murcia, Departamento de Biologia Celular e Histiologia
Cellular polarity plays a fundamental role in tissue organization and homeostasis, and its disruption is closely linked to tumorigenesis. Crumbs3 (CRB3), a conserved polarity protein, is essential for epithelial morphogenesis, tight-junction formation, and barrier function. This review summarizes current knowledge regarding CRB3 expression in normal and malignant human tissues and its dual roles in cancer progression. Systematic immunohistochemical analyses revealed strong CRB3 expression in non-neoplastic glandular epithelia of the gastrointestinal, hepato-pancreato-biliary, renal, and respiratory tracts, as well as in fetal tissues, suggesting its importance in organ development and maintenance. In neoplastic tissues, represented by colorectal adenocarcinoma and oral squamous cell carcinoma, CRB3 expression is preserved or even enhanced compared with normal tissues, which promotes tumor cell migration, triggering invasion/ metastasis as well as cellular proliferation through signaling pathways involving FGFR and RhoA activation. Conversely, previous studies reported that CRB3 functions as a tumor suppressor, based on findings that CRB3 expression induces loss of epithelial mesenchymal transition, whereas loss of CRB3 expression attenuates the integrity of tight junctions, resulting in significantly poorer prognosis in certain cancers. Current data thus suggest that the biological role of CRB3 in tumors is complex. Whether CRB3 acts as a tumor accelerator or suppressor may depend on the individual-specific, unique characteristics of tumor cells. Understanding these dual functions may contribute to the development of novel polarity-targeted therapeutic strategies for cancers of differing origin.
Open Access
Growth factors in mechanisms of malignancy: roles for TGF-í3 and FGF
(Murcia : F. Hernández, 1996) Wright, J.A.; Huang, A.
Malignant progression is a complex process involving the accumulation of multiple genetic alterations leading to changes in many specialized cell functions. Important in this process is the loss of growth control which is frequently associated with modifications in growth factor production, and growth factor response pathways. Indeed, oncogenes have been characterized that code for polypeptide growth factors or their receptors, and many tumor cell populations release potently mitogenic growth factors which contribute to the malignant properties of tumor cells. In this review, the importance of growth factors in mechanisms of malignant progression is emphasized, using as examples the transforming growth factor-beta (TGF-6) and fibroblast growth factor (FGF) families. We describe many of the properties and biological activities of these two families of growth factors, focusing on mechanisms of autocrine and intracrine mitogenic stimulation of tumor cell proliferation and malignant progression. The discussion includes evidence for altered growth factor expression in tumor cells, and the relationship between these changes in growth factors and alterations in the regulation of DNA synthesis, cell proliferation, protease production and cell motility required for invasion and metastasis. Recent studies are described that show that aberrant expression of TGF-BI, bFGF or K-FGF results in dramatic changes in the genetic stability of cells, leading to increased rates of spontaneous gene amplification and the generation of drug resistant variants. These findings describe new malignancy relevant functions for altered growth factor expression.
Open Access
High mobility group A1 and cancer: Potential biomarker and therapeutic target
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Shah, Sandeep N.; Resar, Linda M.S.
The High Mobility Group A1 (HMGA1, formerly HMG-I/Y) gene is highly expressed during embryogenesis and in virtually all aggressive human cancers studied to date, although its role in these settings is only beginning to emerge. Moreover, high levels of expression portend a poor prognosis in some tumors. Increasing evidence suggests that the HMGA1 protein functions as a master regulator with a critical role in normal development and tumor progression in diverse malignancies. These proteins contain AT-hook DNA binding domains that mediate binding to AT-rich regions of chromatin. After binding to DNA, HMGA1 alters DNA structure, and orchestrates the assembly of a transcriptional complex or “enhanceosome” to regulate gene expression. Previous studies indicate that HMGA1 participates in regulating fundamental cellular processes, including transcription, cell cycle progression, embryonic development, neoplastic transformation, differentiation, senescence, viral integration, and DNA repair by virtue of its ability to interact with other proteins, bind to DNA, and modulate gene expression. Recent studies also link HMGA1 expression to poor differentiation status and a refractory, stem cell-like state in aggressive cancers. Together, these findings suggest that HMGA1 could serve as a useful biomarker and therapeutic target in advanced malignancies. Here, we focus on prior studies implicating HMGA1 in the pathogenesis of refractory human tumors arising from diverse tissues and its potential role as a biomarker. We also review previous attempts to target HMGA1 pathways in cancer. Further study of HMGA1 promises to have a major impact on our ability to understand and treat cancer
Open Access
Implications of androgen receptor and FUS expression on tumor progression in urothelial carcinoma
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Abd Raboh, Nermine Mohamed; Adel Hakim, Sarah; Abd El Atti, Rasha Mohamed
Androgen receptor (AR) interact with many pathways involved in bladder cancer development and progression. FUS (fused in liposarcoma), a multifunctional protein essential for different cellular processes, has been demonstrated as a key link between androgen receptor signaling and cell-cycle progression in prostate cancer but has not been examined in urothelial carcinoma (UC) despite an intimate association between prostate and bladder carcinogenesis. Aim. to examine the immunohistochemical expression of AR and FUS in urothelial carcinoma in relation to prognostic parameters and to extrapolate any possible link between the expression of both markers and tumor progression. Study design. Retrospective study using immunohistochemical staining for AR and FUS on (88) cases of urothelial carcinoma. Results. AR shows statistically significant relations with late tumor stage, high tumor grade, and nonpapillary tumor pattern. On the other hand, FUS expression correlates with early tumor stage, low tumor grade and papillary pattern. An inverse relation is found between AR and FUS expression (p=0.001). Cases with high AR IHC expression show statistically significant shorter OS, RFS and PFS compared to cases with low AR expression. Cases with high FUS IHC expression reveal statistically significant longer OS, RFS and PFS compared to cases with low FUS expression. Conclusion. FUS expression is associated with favorable prognostic parameters of UC. A possible interaction is suggested between FUS and AR pathways involved in urothelial cancer progression. Manipulating FUS levels and androgen deprivation therapy can provide new promising targets for treatment trials.
Open Access
Increased expression of 5-lipoxygenase is common in clear cell renal cell carcinoma
(Murcia : F. Hernández, 2007) Faronato, M.; Muzzonigro, G.; Milanese, G.; Menna, C.; Bonfigli, A.R.; Catalano, A.; Procopio, A.
The clinical behaviour of Clear Cell Renal Cell Carcinoma (CC-RCC) is often unpredictable. To fully understand the signaling pathways involved in CCRCC development, we examined whether the 5- Lipoxygenase (5-LO), which catalyzes the biosynthesis of proinflammatory leukotrienes, is involved in renal tumorigenesis. By analyzing 46 snap-frozen primary renal cell carcinomas and their corresponding normal renal cortex biopsies, 5-LO protein levels were found to be significantly increased in the majority of CC-RCCs (P<0.001). Quantitative 5-LO mRNA expression analysis revealed up to 3-fold increased expression in the tumor tissues. There was no association between 5-LO and gender, grade or vein invasion. In contrast, increased 5-LO protein and mRNA correlated with large tumor size (>4 cm) and age of patients (P<0.001). 5-LO was frequently overexpressed in von Hippel-Lindau protein (pVHL)–reduced tumors and in Vascular Endothelial Growth Factor (VEGF)-positive tumors, which represent two frequent alterations in CC-RCC. Cell culture experiments demonstrated that VEGF expression was strongly inducible by 5-LO metabolites in RCC cell lines. The loss of pVHL expression led to high basal 5- LO and VEGF expression, which were markedly reduced by transfection with 5-LO small interfering RNA (siRNA). These results suggest that 5-LO upregulation is an important step in renal cancer progression.
Open Access
Low-grade gliomas clinical and pathobiological aspects
(Murcia : F. Hernández, 2002) Smits, A.
The optimal management of patients with low-grade gliomas remains a challenge for the treating physician. The natural history of the disease shows a large variety, and there is a substantial controversy about many of everyday treatment recommendations. H o w e v e r, new developments in clinical and basic research in neuro-oncology have occurred during the last years. In this review some of these new insights into clinical and biological aspects of low-grade gliomas are discussed, with focus on the translation of new knowledge from basic research into clinical practice. For example, molecular genetic profiling of tumour material has started to guide treatment recommendations and clinical management of some patients with oligodendrogliomas. Experimental studies of the different molecular pathways in tumour cells and in their normal counterparts involved in cell-cycle check-point control have elucidated some of the underlying mechanisms of resistance of gliomas to radiotherapy and c h e m o t h e r a p y. Finally, improved classification of the d i fferent subtypes of low-grade gliomas may be achieved in the near future by characterization of the genetic heterogeneity within the tumour and by identification of a putative stem cell as the origin of the tumour cells.
Open Access
Modulation of the malignant behavior of tongue squamous cell carcinoma cells by matrix metallopeptidase 25 through the NF-κB pathway
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Bai, Shuang; Sun, Shao Kang; Xu, Zhen-Qi; Yan, Ying-Bin; Biología Celular e Histología
Objective. Accumulating evidence has implicated matrix metalloproteinases (MMPs) in the progression of human cancers. Matrix metallopeptidase 25 (MMP25) is a membrane-type MMP whose role in tumorigenesis and cancer development is not well understood. Here, we investigated the functions of MMP25 in tongue squamous cell carcinoma (TSCC). Methods. Gene expression was measured using real-time PCR and western blot. CCK-8 and Transwell assays were used to determine the proliferation, migration, and invasion of TSCC cells. An NK cell co-culture experiment was performed to evaluate the killing of TSCC cells by NK cells. Results. MMP25 had higher expression levels in TSCC tissues than in adjacent non-cancerous tissues. MMP25-overexpressing and MMP25-silenced TSCC cell lines were established by lentiviral transduction. Overexpression of MMP25 promoted proliferation, migration, and invasion of TSCC cells, whereas knockdown of MMP25 had opposite effects. MMP25 modulated the levels of proliferation- and apoptosis-related proteins (PCNA, cyclin D, cyclin B1, p27, and cleaved caspase 3 and 9) and upregulated two invasion-related MMPs (mature MMP2 and MMP9). Additionally, MMP25 promoted tumor growth of TSCC cells in athymic nude mice. Notably, MMP25 upregulated PD-L1 in TSCC cells, attenuated NK cell killing of TSCC cells, and inhibited the secretion of anti-tumor cytokines (TNF-α and IFN-γ). Furthermore, MMP25 promoted the nuclear translocation of NF-κB p65, suggesting that activation of NF-κB signaling may mediate the pro-tumor functions of MMP25 in TSCC. Conclusion. This study revealed a novel role for MMP25 in TSCC, highlighting the potential of MMP25 as a therapeutic target in TSCC.
Open Access
Platelet-Derived Growth Factor PDGF in primary brain tumours of neuroglial origin
(Murcia : F. Hernández, 1998) Smits, A.; Funa, K.
It has become clear that disruptions in the genome of somatic cells play a causative role in tumour development. We know that the ultimate formation of a malignancy is the result of a multistep process in which the functional loss andlor the altered or increased expression of genes play important roles. One such family of genes are the oncogenes, encoding protein products with mainly growth stimulating effects. Platelet-derived growth factor (PDGF) belongs to the family of oncogenes. It is likely that PDGF plays an essential role in the development of at least a subgroup of malignant astrocytic tumours that do not contain amplification of the EGF-receptor. The expression of PDGF a-receptors is related to tumour progression in these tumours, and some of the most malignant tumours were shown to contain amplification of the PDGF areceptor. It is also clear now from several experimental studies that PDGF can drive the transformed phenotype, and that PDGF antagonists, by blocking the PDGF autocrine pathway revert the transformed phenotype of certain tumour cells. Because of the findings that receptor protein tyrosine kinases such as the EGF- and the PDGF-receptor play a crucial role in the development of gliomas, it is possible that inhibitors of the phosphorylation of the protein tyrosine kinases will be future candidates for glioma therapy. They might be able to at least delay the development of a fully malignant glioma. The role of PDGF in other tumours of neuroglial origin in the central nervous system has not been studied as extensively as its role in gliomas. Recent data suggest that also for the primitive neuroectodermal tumours overexpression of the PDGF a-receptor is related to malignancy of the tumours. For other tumours, such as neuroblastomas, PDGF exerts a differentiating rather than a mitogenic function and is an important survival factor. Further studies are needed to elucidate the role of PDGF in these non-glial primary brain tumours. Moreover, for a complete understanding of the role of PDGF in malignancies of the CNS, it is important to explore its function in the development of the normal Offprint requests to: Dr. Anja Smits, Department of Neurology, University Hospital Uppsala, S-751 85 Uppsala, Sweden CNS further.
Open Access
Research progress on the correlation between platelet aggregation and tumor progression
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2024) Chen, Yuyu; Yuan, Jialong; Tang, Faqing; Liu, Qinglin; Huang, Hongjun; Liu, Huan; Liu, Hao
Platelets are generally considered as the main functional unit of the coagulation system. However, more and more studies have confirmed that platelets also have an important relationship with tumor progression. Tumor cells can utilize platelets to promote their own infiltration and hematogenous metastasis, and platelets are activated and aggregated in this process. Therefore, platelet aggregation may be a concomitant marker of tumor progression. This is of great significance for predicting tumor metastasis before timely treatments.
Open Access
The role of proteoglycans in the reactive stroma on tumor growth and progression
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Coulson-Thomas, Yvette May; Gesteira Ferreira, Tarsis; Lawrence Norton, Andrew; W-Y Kao, Winston; Bonciani Nader, Helena; Coulson-Thomas, Vivien Jane
The stroma surrounding tumors can either restrict or promote tumor growth and progression, and both the cellular and non-cellular components of the stroma play an active role. The cellular components in the surrounding stroma include tumor-associated fibroblasts, host tissue cells and immune cells. The noncellular components, which form the extracellular matrix (ECM) scaffold, include proteoglycans, collagen, proteinases, growth factors and cytokines. For tumorigenesis to occur it is necessary for tumor cells to modify the surrounding stroma. Tumor cells have mechanisms for achieving this, such as co-opting fibroblasts and modifying the ECM they produce, degrading the surrounding ECM and/or synthesizing a favorable ECM to support invasion. Proteoglycans are an important component of the ECM and play an active role in tumor growth and progression. The expression and glycosylation patterns of proteoglycans are altered in the stroma surrounding tumors and these molecules may support or restrict tumor growth and progression depending on the type and stage of tumor. In the present review we discuss the difference between the tumor promoting and restricting stromal reactions surrounding tumors and the role proteoglycans play.
Open Access
Tracking prostate carcinoma micrometastasis to multiple organs using histochemical marker genes and novel cell systems
(Murcia : F. Hernández, 2001) Culp, L.A.; Holleran, J.L.; Miller, C.J.
Studies of human prostate carcinoma (PCA) have been hampered by only a few cell systems from already-metastatic human disease. We have developed a novel cell system by using tissue cultured CWR22R cells from a xenograft of a primary tumor from a human patient. These cells were transfected with the bacterial lacZ gene to maximize their detection during progression and metastasis in nude mice. LZ-CWR22R cells are extremely stable for lacZ expression over 25 passages and metastasize to lung, liver, and bone from the subcutis - major sites of metastasis of the human disease. A matrigel vehicle facilitated development of primary tumors and micrometastases in al1 organs. While some micrometastases developed into overt metastases, others remained as micrometastases for long periods of time, possibly providing a model of latency of metastatic disease. An experimental metastasis model (tail vein injection) also generated micrometastases in lung, liver, and bone with differing kinetics of formation and stability. Serial sections of many individual lung micrometastases within one hour of injection indicated considerable heterogeneity in cellular composition (from 1 to 19 cells/site) while liver sites at later times were comprised of only 1 or 2 cells (the size of bone sites were comparable to those of liver). By combining use of these histochemically-tagged PCA cell systems with high resolution molecular analyses (laser-capture microdissection), it will now be possible to analyze gene expression patterns characteristic of micrometastases developing in severa1 different organs.

Browsing by Subject "Tumor progression"

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